DESCRIPTION (Applicant's Abstract): This proposal seeks support for the applicant for a K05 level Research Scientist Award. The application, if funded, would serve to reduce the applicant's teaching and administrative assignments to a minimal level and would increase the time available to the applicant to pursue research. Most of the research that will be carried out during the tenure of this grant will use genetic strategies (classical genetic methods, molecular methods and null mutants/transgenics) to help identify nicotinic receptor subtypes that modulate specific behavioral and neurochemical responses to nicotine. A major goal is to identify mechanisms that explain genetically-based variability in initial sensitivity to nicotine and in the development of tolerance to nicotine. These studies will focus on identifying naturally-occurring polymorphisms in neuronal nicotinic receptor genes in the mouse and on assessing how/whether these polymorphisms alter behavioral and neurochemical responses to nicotine. These studies will be augmented by studies utilizing mice that have had specific nicotinic receptor genes deleted (null mutants). Hopefully, these studies will identify potential mechanisms that would explain how genetic factors influence tobacco use by humans.